Methamphetamine addiction remains a significant public health problem with no known effective pharmacotherapies. Small clinical trials suggest that oral naltrexone, an opioid antagonist with known efficacy in treating alcoholism, has efficacy against amphetamine addiction. In alcoholics, use of sustained release naltrexone improves adherence and decreases drinking. Alcoholics who are carriers of the A118G single nucleotide polymorphism (SNP) of the (-opioid receptor (OPRM1) respond better to naltrexone than do non-carriers. We propose conducting the first trial of naltrexone for methamphetamine addiction. We will use the injectable, sustained release formulation and focus on the role of the A118G SNP in response to naltrexone. The conventional approach to a full-scale outpatient efficacy trial would be to recruit equal numbers of A118G and wild type subjects and assign them randomly to naltrexone or placebo. However, the relative infrequency of the A1118G polymorphism (10-30%) would require screening many subjects (~800), and is not appropriate for a pilot trial. If naltrexone is effective for methamphetamine addiction, we anticipate a large difference in response to naltrexone based on the presence or absence of the A1118G polymorphism. Finding such a difference would indicate that a larger, placebo-controlled trial should be conducted. Therefore, we plan to conduct an outpatient, pilot clinical trial of sustained release naltrexone as a pharmacotherapy for methamphetamine addiction, comparing responses to a sustained release formulation (380 mg, intramuscular, given once per month over two months) of naltrexone in subjects with and without the A118G polymorphism. Comparing the effects of naltrexone in these two groups will provide important data useful in guiding the design of subsequent, more definitive studies. In this pilot trial, we utilize several innovative methods to test naltrexone against methamphetamine addiction. First, we use sustained release naltrexone to improve compliance and decrease variability in drug response. Second, we recruit two pharmacogenomically-defined groups - carriers of the A118G SNP, and wild type - and compare response to naltrexone by pharmacogenomic status. Third, we utilize a non-randomized placebo control group from a similar, simultaneously running parallel study to permit effect size estimation at essentially no cost. Fourth, we investigate putative mechanisms of naltrexone action, which include reduction in craving and impulsivity. Thus, our proposed trial offers a combination of innovative methods, efficiency, and a strong rationale for testing naltrexone against methamphetamine addiction. PUBLIC HEALTH RELEVANCE: Methamphetamine use is a worldwide health problem, and no pharmacotherapy has yet shown much promise in decreasing high rates of relapse seen in methamphetamine dependence. Naltrexone blocks opioid receptors, an action thought to be important in characteristics of drug use such as reinforcement, reward, impulsivity, and craving. We plan to investigate whether a long-lasting, injection form of naltrexone, which has shown efficacy in some groups with alcohol and other drug problems, may help prevent relapse in persons who are methamphetamine dependent.